Viral infection of hepatocytes

• Applicant: Professor Dr. Thomas von Hahn
• Subject Area: Gastroenterology ; Virology
• Term: from 2010 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 155469331

Numerous viral pathogens infect the liver – either exclusively or among other target tissues – causing acute and/or chronic liver damage and a significant global burden of disease. To home in on and infect hepatocytes viral pathogens depend on a limited number of cellular molecules that are essential for viral cell entry (“entry factors”). For the hepatitis C virus (HCV) we and others were able to demonstrate that at least four essential entry factors exist and that these very likely determine both host range and tissue tropism of HCV. It is now becoming clear that some cell surface factors serve several unrelated epitheliotropic pathogens. Several of these “multi-pathogen receptors” such as seem to cluster in the tight junction. We propose to use a lentiviral pseudotyping approach to study hepatocyte infection by three major hepatotropic pathogens: HCV, Hepatitis B Virus (HBV) and Yellow Fever Virus (YFV). We will take a 3-step approach: • Step 1: Establish and characterize a pseudotyping system, • Step 2: Use the pseudotyping system to identify cellular entry factors, • Step 3: Validate entry factor(s) and identify blocking agents. In the case of HCV steps 1 and 2 have already been taken by us and others, so the focus will be on step 3, most notably the characterization of oxidized LDL as a specific blocker of HCV entry. For HBV we will aim to take all 3 steps in full. For YFV focus will be on step 1, however, the scope could be expanded time and resources permitting. Through side-by-side experiments with all three pathogens we will probe for possible common mechanisms of hepatocyte infection. To identify novel antiviral targets, maybe even cross-viral targets, and candidate blocking agents is the long-term goal of this proposal.

• DFG Programme: Independent Junior Research Groups